Human cortical dysplasia and epilepsy: An ontogenetic hypothesis based on volumetric MRI and NeuN neuronal density and size measurements

In epilepsy patients with cortical dysplasia (CD), this study determined the probable ontogenetic timing of pathogenesis based on the number, location and appearance of neurons. Magnetic resonance imaging (MRI) determined gray and white matter volumes of affected and non-affected cerebral hemispheres, and gray and white matter neuronal-nuclear protein (NeuN) densities and sizes were assessed in epilepsy surgery patients (0.2-38 years) with CD (n = 25) and non-CD etiologies (n = 14), and compared with autopsy cases (n = 13; 0-33 years). Pathology group, seizure type and age at surgery were compared against MRI and NeuN data. CD patients demonstrated increased MRI cerebral (3%) and gray matter (8%) volumes of the affected compared with non-affected cerebral hemisphere, and increased layer 1 (131%), upper cortical (9-23%) and white matter (28-77%) NeuN densities compared with autopsy cases. Non-CD cases showed decreased cerebral volumes of the affected hemisphere (14-18%) without changes in NeuN densities. Compared with autopsy cases, in CD and non-CD patients, cortical neurons were hypertrophied. Patients with a history of infantile spasms had a 40% increase in the size of layer 1 neurons compared with cases without spasms. By age, regardless of pathology group, there were logarithmic increases in MRI cerebral and white matter volumes, logarithmic increases in the size of lower gray and superficial white matter neurons, and logarithmic decreases in gray and white matter neuronal densities. These results support the concept that there were more neurons than expected in layer 1, gray, and white matter of CD patients compared with non-CD and autopsy cases. In addition, the location and appearance of neurons are consistent with the hypothesis that CD is the consequence of abnormalities occurring late in corticoneurogenesis that involve excessive neurogenesis with retention of pre-plate cells in the molecular layer and subplate regions.